XIAP inhibits gentamicin-induced hair cell damage and ototoxicity through the caspase-3/9 pathway
| Autor: | Hui-Qun Jie, Dongzhen Yu, Yanmei Feng, Hui Wu, Min Liang, Jingchun He, Jun Yang, Dekun Gao, Karthikeyan Balasubramanian, Guiliang Zheng |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Caspase 3 Mice Transgenic Inhibitor of apoptosis Biochemistry Inhibitor of Apoptosis Proteins 03 medical and health sciences Mice 0302 clinical medicine Organ Culture Techniques Ototoxicity Western blot Hair Cells Auditory medicine Animals Cochlea Caspase Pharmacology biology medicine.diagnostic_test Dose-Response Relationship Drug Chemistry medicine.disease Molecular biology Caspase 9 XIAP Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis biology.protein Hair cell Gentamicins Signal Transduction |
| Zdroj: | Biochemical pharmacology. 186 |
| ISSN: | 1873-2968 |
| Popis: | Gentamicin (GM), an aminoglycoside antibiotic, is one commonly used clinical drugs with ototoxic side effects. One of the most principal mechanisms of its ototoxicity is that GM can activate caspase-mediated cell death pathways in the cochlea. Since the anti-apoptotic protein known as X-linked Inhibitor of Apoptosis Protein (XIAP) has been reported to directly bind to activated caspase protein and inhibit their activities, we hypothesized that it might protect cochlea hair cells from GM ototoxicity. To evaluate this hypothesis, postnatal day 2–3 (P2-3) transgenic (TG) mice, in which XIAP gene is over-expressed under a pure C57BL/6J genetic background was constructed. We first extracted the cochlea tissue of normal mice and treated them with different concentrations of GM, and the number of hair cells were observed to determine the concentration of GM used in subsequent experiments. Next, we used Western Blot experiment to examine the effect of GM on XIAP protein expression in normal mouse cochlea, and then Western Blot and RT-PCR experiments were used to identify the transgenic mice. Finally, immunofluorescence assays were used to detect the effect of GM on the expression of caspase protein and verify the protective effect of XIAP. We found that GM at a concentration of 0.5 mM significantly affected the function of cochlea hair cells, up-regulating the expression of cleaved-caspase-3 and cleaved-caspase-9 protein but down-regulating XIAP protein. In the cochlea tissues of TG mice, this effect of GM was suppressed, and the destruction of hair cells was significantly reduced, and the cleaved-caspase-3 and cleaved-caspase-9 proteins were significantly suppressed. These results suggested that XIAP reduces GM-induced ototoxicity and caspase-3/9 pathway is associated with this process. |
| Databáze: | OpenAIRE |
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